The present invention relates to implantable monitoring systems for monitoring and/or measuring biochemical substances within the body of a patient. More particularly, the present invention is directed to implantable enzyme-based monitoring systems, small enough to be implanted through the lumen of a catheter or hypodermic needle, that measure the amount and rate of change of glucose, in vivo, over an extended period of time.
Glucose is an important source of energy in the body and the sole source of energy for the brain. Glucose is stored in the body in the form of glycogen. In a healthy person, the concentration of glucose in the blood is maintained between 0.8 and 1.2 mg/ml by a variety of hormones, principally insulin and glucagon. If the blood-glucose concentration falls below this level neurological and other symptoms may result, such as hypoglycemia. Conversely, if the blood-glucose level is raised above its normal level, the condition of hyperglycemia develops, which is one of the symptoms of diabetes mellitus. The complications associated with both of these disorders, particularly if left uncorrected, can result in patient death. Thus, measuring and maintaining the concentration of glucose in the blood at a proper level is critically important for good health and longevity.
Unfortunately, some individuals are physically unable to maintain proper glucose levels in their body. For such individuals, the concentration of glucose can usually be altered, as required, to maintain health. For example, a shot of insulin can be administered to decrease the patient""s glucose concentration, or conversely, glucose may be administered, either directly, as through injection or use of an intravenous (IV) solution, or indirectly, as through ingestion of certain foods or drinks.
Before a patient""s glucose concentration can be properly adjusted, however, a determination must be made as to what the current glucose concentration is and whether that concentration is increasing or decreasing. Implantable glucose monitoring systems have been described that are designed to provide continuous measurement of a patient""s glucose concentration. See for example, U.S. Pat. Nos. 3,539,455; 3,542,662; 4,484,987; 4,650,547; 4,671,288; 4,703,756; 4,890,620; 5,165,407; and 5,190,041. Most of these systems are based on the xe2x80x9cenzyme electrodexe2x80x9d principle where an enzymatic reaction, involving glucose oxidase, is combined with an electrochemical sensor, to measure either oxygen or hydrogen peroxide, and used to determine the concentration of glucose in a patient""s blood. It is noted however that the implantable monitoring systems contemplated herein need not be enzyme-based; non-enzyme based (or reactant-based) monitoring systems are likewise contemplated, herein, through enzyme-based systems are preferred.
Generally, enzyme-based glucose monitoring systems, whether implantable or not, use glucose oxidase to convert glucose and oxygen to gluconic acid and hydrogen peroxide (H2O2). An electrochemical oxygen detector is then employed to measure the concentration of remaining oxygen after reaction of the glucose; thereby providing an inverse measurement of the glucose concentration. A second enzyme, catalase, is optionally included with the glucose oxidase to catalyze the decomposition of the hydrogen peroxide to water, in order to prevent interference in the measurements from the H2O2. Alternatively, an electrochemical detector capable of measuring H2O2 may be employed and from that measurement, the concentration of glucose may be determined.
The sensor assembly employed in many enzyme-based glucose monitoring systems has three basic components: an electrode assembly; an immobilized enzyme (glucose oxidase); and one or more membranes isolating these parts from one another and from the sample to be measured. See, for example, U.S. Pat. No. 4,890,620, Gough, David, issued Jan. 2, 1990; U.S. Pat. No. 4,671,288, Gough, David, issued Jan. 9, 1987; and Fischer and Abel, xe2x80x9cA Membrane Combination for Implantable Glucose Sensors. Measurements in Undiluted Biological Fluidsxe2x80x9d, Trans. Am. Soc. Artif. Intern. Organs, 28: 245-248 (1982), each of which is hereby incorporated by reference, in its entirety. In arranging these components, the electrode assembly may either be in direct contact with the immobilized enzyme or it may be, and preferably is, separated therefrom by a membrane. The enzyme is normally immobilized by being associated with a hydrophilic gelatinous layer composed, for example, of polyacrylamide gels, glutaraldehyde-cross-linked proteins or polyhydroxyethyl-methacrylate (PHEMA). Directly adjacent the immobilized enzyme is a hydrophobic membrane, impermeable to glucose. When contacted with the sample to be measured, oxygen diffuses into the hydrophobic outer layer and the gelatinous enzyme layer and glucose diffuses only into the gelatinous enzyme layer, thereby preventing a deficit of oxygen, which could result in an inaccurate measurement of the glucose concentration.
Two particular areas of weakness in this sensor assembly configuration, that contribute to the short life of the implantable enzyme-based glucose monitoring systems, are the finite life of the solid, immobilized enzyme layer and the finite life of the electrode assembly. Once the enzyme layer is either expended by the enzymatic reaction or inactivated by prolonged exposure to body temperatures, the entire monitoring system must be explanted and replaced. Similarly, if the electrode assembly contained within the sensor assembly ceases to function properly, for example due to pH changes at the active surface of the electrodes which may be caused by corrosion of the electrodes, again, the entire monitoring system must be replaced. Further, before the electrode assembly completely wears out, the monitoring system may require frequent recalibration to account for the assembly""s deterioration. Presently, the maximum life expectancy of such monitoring systems is approximately 18 to 24 months, with recalibration required every three to six months, meaning that every couple of years, the patient must undergo surgery to remove and replace the implanted monitoring system.
Another problem with the prior art implantable glucose monitoring systems concerns their accuracy and efficiency. While the electrode assembly of these monitoring systems, which is preferably affixed to a substrate within the system, is within the patient""s body, the data collected by the electrode assembly must be transmitted the length of the monitoring system""s leads to the outside of the patient""s body to be processed. This means the nigh impedance electrode assembly sends its weak signal a significant distance before that signal is processed. This is highly inefficient and may result in unusable and/or inaccurate readings.
Thus, what is needed are implantable monitoring systems that may remain implanted for long periods of time and that provide reliable, accurate measurements over that period of time with infrequent or no recalibrations required. Further, the monitoring system should remain as small as possible in order to maximize its usefulness as an implantable medical device.
The subject matter described and claimed herein advantageously addresses these and other needs by providing an implantable monitoring system having a microprocessor assembly associated therewith in close proximity to the electrode assembly thereof, and/or having means within the system to replenish the enzyme solution and/or electrolyte solution used therein. These improvements result in a monitoring system that is suitable for long-term in vivo use to measure the concentration of one or more prescribed substances (or analytes), such as glucose. In particular, described and claimed herein are implantable monitoring systems having one or more of the following improvements: means for replenishing the enzyme and/or other reactants as they are consumed by the enzymatic and/or other chemical reactions of the system; means for replenishing one or more reagents used within the system, particularly the electrolyte solution bathing the electrode assembly, thereby keeping the concentration of the reagent(s) constant; and signal processing means proximally associated with the electrode assembly for boosting and/or analyzing the data detected by the electrode assembly.
In preferred embodiments, a microprocessor assembly is affixed to the opposite side of the substrate upon which the electrodes-are located. The microprocessor assembly is hermetically sealed on the substrate by, for example, covering the assembly with a metal can which is heat bonded to the substrate. Hermetic feed-throughs within the substrate electrically connect the electrode assembly to the microprocessor assembly, thereby quickly and efficiently transmitting the data collected by the electrode assembly to the microprocessor assembly. This configuration permits the high impedance electrode assembly to send its weak signal only a very short, well insulated distance to the microprocessor attached to the substrate. The microprocessor assembly then boosts the received signal, for example, by digitizing it before sending it out over the monitoring system leads.
In further preferred embodiments, a reservoir of reactant solution, in fluid communication with a reaction chamber located proximate the working electrode of the sensor assembly, is employed to provide a constant supply of unused reactant solution to the sensor assembly. Most preferably the reactant solution comprises an enzyme solution and the monitoring system is an enzyme-based one. Similarly, preferred embodiments described and claimed herein, employ a reagent reservoir system to provide a constant supply of reagent(s) to the monitoring system. In particular, an electrolyte solution is used to bathe the electrodes of the sensor assembly. Thus, an electrolyte reservoir system is employed to provide a constant supply of electrolyte solution to the electrodes, thereby extending the useful life of the electrolyte by, for example, diluting the by-products of electrode corrosion, and thus maintaining the pH of the environment of the electrodes.
Further provided herein is an enzyme solution comprising polymer microspheres in association with a prescribed enzyme, such as glucose oxidase. Association of the prescribed enzyme with the microspheres advantageously maintains a desired enzyme concentration, prevents leakage of the enzyme from the sensor assembly and increases the longevity, reliability and accuracy of the enzyme-based monitoring system.
Also provided herein is a method of extending the useful life of an implantable monitoring system, which method comprises providing means, within the system, to replenish the reactant and/or reagent solutions, particularly enzyme and electrolyte solutions.
These and other objects, features and advantages of the present invention will become apparent to those skilled in the art upon a reading of the following detailed description when taken in conjunction with the drawings wherein there is shown and described illustrative embodiments of the invention.